Recent developments in epigenetic cancer therapeutics: clinical advancement and emerging trends

Abstract

Epigenetic drug discovery field has evidenced significant advancement in the recent times. A plethora of small molecule inhibitors have progressed to clinical stage investigations and are being explored exhaustively to ascertain conclusive benefits in diverse malignancies. Literature precedents indicates that substantial amount of efforts were directed towards the use of epigenetic tools in monotherapy as well as in combination regimens at the clinical level, however, the preclinical/preliminary explorations were inclined towards the identification of prudent approaches that can leverage the anticancer potential of small molecule epigenetic inhibitors as single agents only. This review article presents an update of FDA approved epigenetic drugs along with the epigenetic inhibitors undergoing clinical stage investigations in different cancer types. A detailed discussion of the pragmatic strategies that are expected to steer the progress of the epigenetic therapy through the implementation of emerging approaches such as PROTACS and CRISPR/Cas9 along with logical ways for scaffold fabrication to selectively approach the enzyme isoforms in pursuit of garnering amplified antitumor effects has been covered. In addition, the compilation also presents the rational strategies for the construction of multi-targeting scaffold assemblages employing previously identified pharmacophores as potential alternatives to the combination therapy.

One Omics Approach Does Not Rule Them All: The Metabolome and the Epigenome Join Forces in Haematological Malignancies

“…On the other hand, epigenetics acts at the genome scale by regulating multiple loci at the same time, and thus the targeting of individual epigenetic enzymes has an effect on a multitude of genes, reducing the likelihood of developing resistance. Reflecting this, epigenetic treatments are now part of the standard of care for several haematological malignancies; DNMT inhibitors are currently used for the treatment of AML and MDS, and HDACs are FDA-approved for the treatment of MM, CTCL, and peripheral T-cell lymphoma [374]. Additionally, at the time that this review was written, there were 83 registered clinical studies for epigenetic inhibitors in cancer (https://clinicaltrials.gov/; accessed on 6 July 2021).…”

Emerging Roles of SKP2 in Cancer Drug Resistance

“…These techniques can be applied to induce drug-resistance-cause protein degradation through the ubiquitin proteasome pathway by recruiting an E3 ligase to ligate the target protein for degradation. For instance, it has been reported that E3 ligase cereblon (CRBN) is highly expressed in lung cancer; thus, ligands for CRBN (lenidomide, thalidomide, pomalidomide) could be mounted in the PROTAC model to develop an anti-cancer therapy [ 147 ]. Likewise, the over-expression of Skp2 is observed in multiple cancers, as such the ligands for Skp2 in these cancers could be accommodated to target Skp2.…”

KDM4 Involvement in Breast Cancer and Possible Therapeutic Approaches

“…Since epigenetic machinery such as DNA methylation and histone modifications often work in parallel, the use of single agents in combination has recently drastically increased as this approach enhances their efficacy (102). Such a drug combination approach has also been exploited toward non-epigenetic targets (103). For example, combinations of HDAC-HSP90 inhibitors (104), HDAC-DNMT inhibitors (105), HDAC-KDM1 inhibitors (106), HDAC-BET protein inhibitors (107,108), HDAC-EZH2 inhibitors (109), and HDAC-PI3K inhibitors (110) showed good efficacy in different cancer cells.…”